The pandemic coronavirus disease 2019 (COVID-19) has caused a high mortality rate and poses a significant threat to the population. The disease may progress with mild symptoms or may cause the need for intensive care, depending on many factors. In this study, it was aimed to determine if there is a tendency due to genetic factors in COVID-19 patients. Ninety-four of 188 patients with mild clinical and 94 with severe clinical symptoms were included in the study. The targeted panel including coagulopathy (F2, F5), viral invasion (ACE2), and inflammation (CXCL8, IFNAR2, IFNL4, IL10, IL2, IL6, IRF7, TLR3, TLR7, TNF) related genes was performed sequenced by the next generation sequencing (NGS). The variants found were classified and univariate analyses were performed to select candidate variables for logistic model. Risk factors and variants were compared. It was revealed that the presence of 2 or more risk factors caused the disease to progress severely (p < 0.001). Heterozygous IRF7:c.1357−23dup variant had a 2.5 times higher risk for mild disease compared to severe disease. Other variants were found to be more significant in mild disease. Since polymorphic variants were not evaluated in the literature, the findings of our study could not be compared with the literature. However, as variants that may be effective in the severity of infections may differ according to ethnicity. This study has the feature of being a guide for subsequent studies to be carried out especially in Turkish population. Clinical course of the COVID-19 is likely to depend on a variety of risk factors, including age, sex, clinical status, immunology and genetic factors.
Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of 14C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-β1 (TGF-β1) was assessed in vitro. We found that ACNU significantly inhibited TGF-β1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.
We report an infant case of transient distal renal tubular acidosis and Fanconi syndrome caused by rotavirus gastroenteritis. A 10-month-old boy was admitted to the hospital because of frequent vomiting, lack of vitality, and dehydration. He was diagnosed with rotavirus gastroenteritis on account of his positive stool rotavirus antigen test. Although he presented with acidemia and severe mixed metabolic acidosis, he also had a urine pH of 6.0, indicating impaired urinary acidification. Therefore, he was diagnosed with distal renal tubular acidosis. On the third day of hospitalization, a relatively low %tubular reabsorption of phosphate level with hypophosphatemia, increased fractional excretion of uric acid with hypouricemia, and high urinary β2-microglobulin levels were observed. Moreover, he was diagnosed with Fanconi syndrome on account of multiple proximal tubular dysfunctions. After remission of rotavirus gastroenteritis, the signs of renal tubular dysfunction improved. This was a case of rotavirus gastroenteritis-caused transient distal renal tubular acidosis and Fanconi syndrome. Severe metabolic acidosis resulted from anion-gap metabolic acidosis due to acute kidney injury by rotavirus gastroenteritis and normal anion-gap acidosis due to renal tubular acidosis. When renal tubular acidosis is associated with a disease that causes anion-gap metabolic acidosis, mixed metabolic acidosis occurs and becomes exacerbated. Furthermore, it is important to consider the complications of renal tubular acidosis in the case of severe metabolic acidosis.
A new beta TiNbSn alloy with a low Young’s modulus of approximately 40 GPa has been developed to resolve the stress shielding by Young’s modulus divergence. In this study, the efficacy of TiNbSn alloy locking plates on bone repair is compared to that of commercially pure titanium (CP-Ti). The TiNbSn alloy and CP-Ti, which have Young’s moduli of 49.1 GPa and 107 GPa, respectively, were compared. Male Japanese white rabbits were anesthetized, and osteotomy and osteosynthesis with locking plates were performed on the right tibia. The bone repair was assessed using micro-computed tomography (CT), histomorphometry, immunohistochemistry, and mechanical testing. Micro-CT, histomorphometry, immunohistochemistry, and mechanical testing were performed four weeks after osteotomy. Six weeks after surgery, micro-CT and mechanical testing were performed. Micro-CT analysis at four weeks after surgery showed that the intramedullary fracture callus in the TiNbSn alloy group had more bone volume and numerous bridging structures compared to the CP-Ti group (CP-Ti vs. TiNbSn alloy, 34.3 ± 13.1 mm3 vs. 61.3 ± 19.6 mm3, p = 0.02; mean ± standard deviation). At four weeks post-osteotomy, the healed tibia showed significantly higher strength in the TiNbSn alloy group compared with CP-Ti (CP-Ti vs. TiNbSn alloy, 81.3 ± 31.2 N vs. 133.7 ± 46.6 N, p = 0.04). TiNbSn alloy locking plates had a more positive impact on bone formation and bone strength restoration than the CP-Ti locking plates during the early phase of bone healing.
Cell division control protein 42 (CDC42) modulates insulin secretion and angiogenesis to participate in the pathology of diabetic complications and retinal vascular-associated diseases. This study intended to explore the role of CDC42 in the progression of diabetic retinopathy, and the underlying mechanism. Human retinal microvascular endothelial cells (hRMECs) were cultured in 5.5 mM glucose (normal glucose) or 25 mM glucose (high glucose; HG) medium, respectively. CDC42 overexpression plasmid and small interference RNA (oe-CDC42 and si-CDC42) or corresponding negative controls (oe-NC and si-NC) were transfected into hRMECs under HG. Then, platelet-activating factor C-16 (C16-PAF) (MEK/ERK pathway activator) was added to si-CDC42 or si-NC transfected hRMECs under HG. Our study showed that HG increased CDC42 mRNA and protein, cell viability, invasive cell count, branch points, and tube length but reduced cell apoptosis in hRMECs. CDC42 upregulation enhanced cell viability, invasive cell count, branch points, tube length, p-MEK, and p-ERK, but attenuated cell apoptosis. Downregulation of CDC42 exhibited opposite trends. In addition, C16-PAF also increased cell viability, invasive cell count, branch points, and tube length, p-MEK, and p-ERK, but retarded cell apoptosis. Notably, C16-PAF diminished the effect of CDC42 downregulation on the above-mentioned functions in hRMECs under HG. Conclusively, CDC42 promotes HG-induced hRMEC viability and invasion, as well as angiogenesis, but inhibits apoptosis by activating the MEK/ERK pathway, which may be responsible for the progression of diabetic retinopathy.
Pancreatic fistula is a potentially morbid complication after distal pancreatectomy. Chronic glucocorticoid use is one of the risk factors for pancreatic fistula in pancreaticoduodenectomy, though it has not been reported in distal pancreatectomy. We explored whether chronic glucocorticoid use can be a risk factor for pancreatic fistula in distal pancreatectomy. We reviewed 408 consecutive patients who underwent elective distal pancreatectomy from 2011 to 2021. We evaluated two kinds of pancreatic fistula (postoperative pancreatic fistula and delayed pancreatic fistula). We defined delayed pancreatic fistula as a patient who was re-admitted for pancreatic fistula after the first discharge from the hospital. Preoperative characteristics and postoperative outcomes were analyzed. Two hundred sixty-seven patients underwent open distal pancreatectomy, while 141 patients had laparoscopic distal pancreatectomy. A comparison of patient with and without chronic glucocorticoid use showed that only patients with chronic glucocorticoid use developed delayed pancreatic fistula (0% vs. 16.7%; p < 0.001). In addition, delayed pancreatic fistula occurred in only laparoscopic distal pancreatectomy patients with chronic glucocorticoid use (0% vs. 25.0%; p < 0.001). Although sample size is small, it is reasonable to presume that chronic glucocorticoid use is a potential risk factor for delayed pancreatic fistula in laparoscopic distal pancreatectomy.
The systemic inflammatory response is associated with tumor promotion and suppression. Accumulating evidence shows that peripheral blood markers of inflammatory response predict clinical outcomes in various human cancers. The aim of this study was to investigate the prognostic relevance of the inflammation-based biomarkers in colorectal cancer (CRC). We retrospectively analyzed 118 CRC patients who underwent curative resection between 2012 and 2017. The inflammation-based biomarkers were evaluated by using preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), prognostic nutritional index (PNI), and Glasgow prognostic score (GPS). Prognostic values were assessed by the Kaplan-Meier analysis for cancer-specific recurrence-free survival (RFS) and Cox proportional-hazards model. There were significant differences in the levels of NLR, PLR, SII, and SIRI between recurrence and non-recurrence group. The area under the curve (AUC) for SII was 0.710, which showed the highest value in the inflammation-based biomarkers. Multivariate analysis identified that SII (p = 0.0031) and lymph node metastasis (p = 0.0168) were independent prognostic factors for recurrence. High SII exhibited more dismal RFS than low SII in CRC patients with non-metastatic lymph node (p = 0.0002). Our study suggests that SII and lymph node metastasis could be useful indicators in predicting the recurrence of CRC patients. Additionally, SII could accurately stratify CRC patients with tumor recurrence by combining with lymph node metastasis. This result would be beneficial for determining the optimal therapeutic strategies after surgical resection for CRC.
Vasohibin-2 (VASH2), a homologue of vasohibin-1 (VASH1), is overexpressed in various cancer cells and promotes tumor progression. We therefore regard VASH2 as a molecular target for cancer treatment. Here we applied vaccine technology to develop a therapy against VASH2. We selected two amino acid sequences of VASH2 protein; the MTG and RRR peptides, which contain possible B cell epitopes. These sequences are identical between the human and murine VASH2 proteins and distinct from those of the VASH1 protein. We conjugated these peptides with the carrier protein keyhole limpet hemocyanin, mixed with an adjuvant, and injected subcutaneously twice at a 2-week interval in mice. Both vaccines increased antibodies against the antigen peptide; however, only the MTG peptide vaccine increased antibodies that recognized the recombinant VASH2 protein. When Lewis lung cancer (LLC) cells were subcutaneously inoculated, tumors isolated from mice immunized with the MTG peptide vaccine showed a significant decrease in the expression of epithelial-to-mesenchymal transition (EMT) markers. EMT is responsible for cancer cell invasion and metastasis. When the LLC cells were injected into the tail vein, the MTG peptide vaccine inhibited lung metastasis. Moreover, the MTG peptide vaccine inhibited the metastasis of pancreatic cancer cells to the liver in an orthotopic mouse model, and there was a significant inverse correlation between the ELISA titer and metastasis inhibition. Therefore, we propose that the MTG peptide vaccine is a novel anti-metastatic cancer treatment that targets VASH2 and can be applied even in the most malignant and highly metastatic pancreatic cancer.
Web-based post-bereavement survey systems for specialized palliative care will enable obtaining timely results on the care quality from more participants at a lower cost. The primary aim of the study was to develop a web-based post-bereavement survey system and to compare response rates for different number of items. The secondary aim was to examine response bias between web-based and mail survey in post-bereavement surveys. Between January and April 2019, two cross-sectional web-based questionnaire surveys were conducted among the bereaved families from six inpatient palliative care units in Japan. Measurements included structure and process of end-of-life (EOL) care, overall care satisfaction, achievement of a good death, depression, grief status, web survey usability, and participant and bereaved family member characteristics. The long survey included 34 items, and the short survey included 16 items. There were no significant differences in the response rates between the long and short surveys (24% and 27%, respectively, p = 0.376). Compared with a previous nationwide post-bereavement mail survey, more children responded; however, the quality rating scores was unchanged. Despite low response rate, no apparent response bias was observed, indicating its feasibility. This survey method is low-cost, less burdensome to the institution, and allows for ongoing quality assurance.